Optimizing Therapy in Progressive MS: Treatment Options

Transcription

1 Optimizing Therapy in Progressive MS: Treatment Options Neeta Garg, MD Associate Professor of Neurology University of Massachusetts Medical School Associate Director, Multiple Sclerosis Center UMass Memorial Medical Center

2 Multiple Sclerosis Multiple sclerosis is a potentially treatable disorder The recent focus has been on the early diagnosis and treatment Disease modifying therapy can slow down the progression of disability May delay the development of clinically definite MS

3 Definition of MS Subgroups Relapsing-remitting MS: clear relapses with full recovery or with residual deficit; lack of disease progression in periods between relapses Primary-progressive MS: disease progression from onset with occasional plateaus and temporary minor improvement without relapses Secondary-progressive MS: initial RR course followed by progression with or without occasional relapses, minor remissions and plateaus Progressive-relapsing MS: progressive disease from onset, clear acute relapses, continued progression between relapses Lublin and Reingold, Neurology 1996; 46,

4 MS: Clinical Subtypes Relapsing-remitting Secondary progressive Symptoms Time Symptoms Time Symptoms Time Symptoms Time Primary progressive Progressive-relapsing Symptoms Time Symptoms Time Symptoms Time Symptoms Time Lublin FD, et al. Neurology. 1996;46: Kieseier BC, et al. Semin Neurol. 2003;23: Overview of MS

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6 Multiple Sclerosis Disease activity heterogeneous and course variable First-line therapy: partially effective, 30% relapse reduction with DMT: stabilization vs. continuous activity in some patients About 50 percent of people with relapsingremitting MS may progress to SPMS within ten years and up to 80 to 90% of people with RRMS would eventually develop SPMS within 25 years slow progressive accumulation of disability fewer or no relapses

7 Optimizing therapy in progressive MS However, this was before the wide-spread use of disease-modifying medications Before DMTs became widely available, the long-term effects of these medications on the progression of MS still not known Proportion of progressive disease probably much lower and slower to develop now

8 MS: Natural history In 60% of patients, MS begins as a relapsing-remitting disease and evolves secondarily into a progressive neurological illness Up to 40% of patients with attacks severe enough to render them nonambulatory may not recover At 15 years from MS onset, 50% of patients are disabled to the point at which they at least require a cane to walk a half block Early age at onset, female sex, relapsing-remitting course at onset, and perhaps optic neuritis or sensory symptoms at onset and relatively few attacks in the first two years are associated with a favorable course Weinshenker et al, Ann Neurol. 1994;36 Suppl:S6-11

9 MS and Disability Fifteen years after diagnosis: 80% of patients have functional impairment 50% of patients are unable to walk 70% of patients are unable to continue working PDRHealth. Multiple Sclerosis. Available at: Overview of MS

10 Key Parameters in MS Management: Disability Expanded Disability Status Scale Death Normal neurological exam Minimal disability Increased limitation in walking ability Need for walking assistance Restriction to wheelchair Helpless bed patient Patient disability classification Expanded Disability Status Scale (EDSS) = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MS Kurtzke JF. Neurology. 1983;33: Overview of MS

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12 MS: Natural history Patients with definite relapsing-remitting MS at British- Columbian MS clinic before July 1998 were selected from the population-based database Prognosis and risk factors for progression to and from SPMS were examined Results 87.6% were relapsing-remitting (RR) at onset, 58.2% reaching SPMS, at median 18.9 years The RR phase lasted on average almost two decades, being shorter for males and those older at onset of MS A longer RR phase was a favorable predictor of disease progression in SPMS Longer disease duration, older age, and lower EDSS at onset of SPMS: slower progression to higher disability Tremlett et al, Mult Scler Apr;14(3):314-24

13 MS: Natural history The relationship of relapses to long-term disability in multiple sclerosis is uncertain Relapse reduction is a common therapeutic target but dissociation between relapse suppression and disability accumulation exists Relationships between relapses and disability progression in the preprogressive or relapsing-remitting phase for outcomes of disability (requiring assistance to walk, being bedridden and dying from multiple sclerosis [Disability Status Scale 6, 8, 10) was investigated Results: Frequent relapses in the first 2 years and shorter first inter-attack intervals predicted shorter times to reach hard disability endpoints Time to Disability Status Scale 3 highly and independently predicted time to Disability Status Scale 6, 8 and 10 In contrast, neither total number of relapsing-remitting phase attacks nor of relapses experienced during the relapsing-remitting phase after the second year up to onset of progression showed correlation with progression of disability Scalfari et al, Brain Jun 9. [Epub ahead of print]

14 MS: Natural history Relapse frequency beyond Year 2 does not appear to predict the key outcome of secondary progression or times to higher disability highlighting two distinct disease phases related to late outcome These appear to be separated by a watershed within the relapsing-remitting phase, just a few years after clinical onset Higher early relapse frequencies and shorter first inter-attack intervals herald more rapid deterioration via interaction with the neurodegeneration characterizing secondary progression Scalfari et al, Brain Jun 9. [Epub ahead of print]

15 How to diagnose progressive disease

16 Progressive disease: Diagnosis Subjective Worsening symptoms with or without continued attacks Increasing disability Physical Cognitive Objective Increased number and severity of relapses Worsening (sustained) baseline disability Walking: 25-foot walk time Hand function: 9-hole peg time Cognitive impairment Greater lesion burden on MRI

17 Key Parameters in MS Management MRI Activity and Area Assesses MS disease activity in the brain and helps track disease progression* Relapse With each relapse in MS, the probability of permanent disability increases Disability Progression The unpredictable course of MS eventually leads to significant functional disability for many patients *The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown. Overview of MS

18 Definition of Breakthrough disease Clinical activity in 6 months after therapy Occurrence of a confirmed relapse with findings on neurologic examination consistent with the symptoms or Objective neurologic impairment (1-point increase in EDSS) MRI activity is defined as appearance of Combined unique activity (CUA) CAU: Number of lesions that were new or enlarging in T2- weighted images and Gd enhancing lesions Durelli et al, J Neurol Neurosurg Psychiatry 2008;79: Rio et al, Mult Scler 2008;14:

19 Key Parameters in MS Management: Relapse Relapse = New or worsening symptoms, lasting >24 hours in the absence of fever, attributed to MS activity, preceded by stability or improvement for 30 days. 1 Common clinical trial outcome measures: Relapse rate Time to relapse Risk of relapse Percent of patients remaining relapse free 1. Schumacher GA, et al. Ann NY Acad Sci. 1965;122: Overview of MS

20 Key Parameters in MS Management: MRI T1-weighted scan with gadolinium (Gd) enhancement Shows number of new lesions (currently active disease) T2-weighted scan Shows number and size of new as well as older (inactive) lesions The exact correlation between MRI findings and the current or future clinical status of patients, including disability progression, is unknown. Overview of MS

21 MS: Breakthrough disease Disease activity is highly heterogeneous among patients with multiple sclerosis Average reduction in relapse rate of 30% induced by interferon (IFN)- treatment encompasses stabilization of disease in some patients and continuous disease activity in others The effect of IFN is provable on MRI even within the first weeks of treatment Presence of MRI disease activity within the first 6 12 months treatment appears predictive of subsequent clinical disease activity Nonresponders: High-titer of Nabs or other factors for biologic nonresponse Inherent high disease activity may underlie on-treatment disease activity Durelli et al, J Neurol Neurosurg Psychiatry 2008;79: Rio et al, Mult Scler 2008;14: , Hesse et al, Neurology 2010;74;

22 MS: Breakthrough disease In published phase III trials 62% to 75% of patients with relapsing-remitting MS had one or more relapses within two years while on disease-modifying drug therapy about one fourth had a sustained increase in Expanded Disability Status Scale score one fourth had one or more gadolinium (Gd)-enhancing lesions more than half had one or more new T2 lesions Rudick et al, CNS Drugs. 2008;22(10): Malucchi et al, Neurology. 2008;70(13 pt 2):

23 Therapeutic Options

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26 Other Therapy Options for MS Other potential MS therapies Corticosteroids Cyclophosphamide (Cytoxan ) Azathioprine (Imuran ) Methotrexate Mycophenolate mofetil (Cellcept ) Monoclonal antibodies Intravenous immunoglobulin G (IVIG) Plasmapheresis Cladribine

27 Case history 64 yo male with progressive leg stiffness, weakness, walking difficulties, and urinary urgency and hesitancy for last 20 years Started using cane 10 years ago, currently able to walk with the cane although walking slower and limited for last 2 years Exam: moderate spasticity and weakness in legs with ataxia CSF: positive OCB and elevated IgG index

28 Cervical MRI: T2WI

29 Thoracic MRI

30 Primary Progressive MS

31 PPMS: Natural history Seen in 10-15% of patients Age of onset 10 years older than RRMS (40 vs 30) Peak age of onset of years for men versus years for women Different sex ratio (M:F=1:1.3), men affected more frequently in PPMS than RRMS (M:F = 1:3) This distinction also blurs with advancing age of onset Weinshenker et al, Brain 1989, Cottrell et al, Brain 1999 Ebers GC, Neurol Sci 2000, Tremlett et al, Neurology 2005

32 Primary Progressive MS Seen in 10-15% of patients Age of onset 10 years older than RRMS (40 vs 30) Peak age of onset of years for men versus years for women Different sex ratio (M:F=1:1.3), men affected more frequently in PPMS than RRMS (M:F = 1:3) This distinction also blurs with advancing age of onset

33 PPMS: Clinical presentation Progressive myelopathy in 80-90% over monthsyears Less common: Pancerebellar syndrome with progressive ataxia Rarely progressive visual loss due to optic neuropathy Cognitive impairment with attention, working memory, and other deficits frequently seen with any presentation

34 PPMS: Disease modifying therapy PROMise (Placebo-controlled trial of glatiramer acetate in PPMS): largest study in PPMS Randomized, placebo-controlled 3 year trial 943 patients, Glatiramer acetate vs. placebo Number of patients with sustained increase in disability low No significant reduction in treatment arm Study stopped at 2 years Subgroup analysis showed some effect in males Wolinsky et al, Ann Neurol 2007

35 PPMS: Treatment Corticosteroids tried empirically, no evidence Beta-interferon Study IFN-β-1a of 50 patients: no effect on disability, brain or spinal cord atrophy (Leary et al, Neurology 2003) IFN-β-1b studied in 73 patients: non-significant trend for disability (EDSS) and significant effect on MSFC (Montalban X, Mult Scler 2004, suppl)

36 PPMS: Treatment Placebo-controlled trial of mitoxantrone (Kita et al, Neurology 2004, abst.) Negative Cladribine Not effective in PPMS and SPMS (Rice et al, Neurology 2000) Methotrexate (low dose-7.5 mg weekly) Small beneficial effect on arm function (Goodkin et al, Ann Neurol 1995) IVIG PPMS patients showed a slight favorable IVIG effect on the best EDSS score (Pohlau et al, Mult Scler. 2007;13(9): ) Riluzole Stabilization of cervical cord area and T1 lesion volume in 16 patients (Kalkers et al, Mult Scler 2002)

37 Rituximab (Rituxan ) in PPMS OLYMPUS trial: Phase II/III randomized, double-blind, placebocontrolled, multi-center study was designed to evaluate the efficacy, safety and tolerability of four courses of Rituximab in patients with PPMS Study of 439 patients for 96 weeks, Rituximab didn't significantly slow the course of the disease Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010) those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007) and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo Hawker et al, Ann Neurol Oct;66(4):460-71

38 PPMS: Treatment Uncontrolled studies: disease stabilization Autologous hematopoetic stem cell transplantation (Saccardi et al, Mult Scler 2006) Cyclophosphamide (Zephir et al, J Neurol Sci 2004)

39 PPMS: Future therapies Ongoing trials FTY720 or Fingolimod in Patients With Primary Progressive Multiple Sclerosis (INFORMS) Canabinoids: phase III study in UK Natalizumab Treatment of Progressive Multiple Sclerosis (NAPMS): phase II trial to study safety and efficacy of natalizumab in treatment of primary and secondary progressive multiple sclerosis Double Blind Placebo-Controlled Phase I/II Clinical Trial of Idebenone (compound similar to coenzyme Q10) in Patients With Primary Progressive Multiple Sclerosis

40 Secondary Progressive MS

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42 SPMS: Mitoxantrone Mitoxantrone (Novantrone ) has cytotoxic and immunosuppressive effects and has been used for the management of acute myeloid leukemia and symptomatic hormone-resistant prostate cancer MIMS trial: Effect of mitoxantrone in 194 patients with worsening RRMS or SPMS studied At 2 years, the mitoxantrone group experienced benefits compared with the placebo group for the primary outcome: multivariate composite consisting of EDSS change, Ambulation Index change, the number of treated relapses, the time to the first treated relapse, and the change in the Scripps Neurologic Rating Scale Mitoxantrone at a dose of 12 mg/m2 given every 3 months reduces progression of disability and clinical exacerbations To avoid cardiotoxicity, it is recommended that a lifetime cumulative dose of 140 mg/m2 should not be exceeded

43 SPMS: Beta-IFN-1b The European trial In the treatment arm a significant reduction of the confirmed 1-point EDSS progression rate was found The clinical and MRI attack rates and the volume of white matter disease as seen on MRI were significantly reduced Subgroup analysis of patients who did or did not experience clinical attacks in the 2 years before study initiation, or who did or did not have attacks during the study, demonstrated similar effects of IFN beta-1b The benefit, however, in patients with EDSS 6.0 was less convincing. North American trial The study design was similar but the trial failed to demonstrate a statistically significant reduction in the confirmed 1-point EDSS progression rate The reason for this discrepancy between these two trials is unclear It is possible that the North American cohort of patients had more advanced disease and significantly fewer superimposed attacks than their European counterparts and that IFN beta is most effective in the relapsing phase of the disease, but this is speculative European study group on IFN-beta-1b in SPMS, Lancet 1998;352:1491 7

44 SPMS: Beta-IFN-1a Similarly, the trial of subcutaneous IFN beta-1a in SPMS (the SPECTRIMS trial) failed to find a statistically significant reduction in the confirmed 1- point EDSS progression rate In a post hoc subgroup analysis, separating patients into those with or without relapses, a beneficial treatment effect on the confirmed 1- point EDSS progression rate was noted (P = 0.027) in patients with attacks The effect of intramuscular IFN beta 1a was investigated in 436 subjects with SPMS and EDSS 3.5 to 6.5 in the IMPACT trial IFN beta-1a was found to be beneficial (P = 0.033), an effect driven mainly by the nine-hole peg test, whereas there was no discernible benefit on the EDSS Patients in the treatment arm experienced 33% fewer relapses (P = 0.008) (SPECTRIMS) Study Group Neurology 2001;56:

45 SPMS: Beta-interferon The results of interferon b trials in patients with SP-MS have thus been mixed This is particularly striking with the two Betaseron studies, which appear superficially similar and use an identical interferon b product administered with the same dose schedule The European study showed a highly significant, though modest, benefit on disability progression, whereas the North American Study showed no differences This discrepancy has led to comparison between the two study populations. The North American population was significantly older at entry, had a longer disease duration, fewer relapses in the previous 2 years, greater change in EDSS in the 2 years before study entry, and fewer MRI enhancing lesions at study entry These differences suggest that the North American population showed less inflammation and possibly more noninflammatory axonal degeneration

46 SPMS: Beta-interferon Although speculative, this analysis would conclude that interferon b therapy is most effective in the earlier inflammatory stage of MS, and increasingly less effective in later stages characterized by progressive disability In conclusion, it is appropriate to consider IFN beta for treatment with SPMS patients still experiencing relapses (Type A) The FDA has approved IFN beta-1b for SPSM, and the European agency EMEA has approved IFN beta-1b and subcutaneous IFN beta-1a for SPSM with superimposed relapses. The utility of IFN beta in patients with SPMS that do not suffer superimposed relapses is uncertain at present (Type U)

47 SPMS: Dirucotide (MBP8298) Dirucotide induces antigen-specific immunological tolerance Phase 3, double-blind, randomized, placebocontrolled trial MAESTRO-01 Failed to meet the primary endpoint of delaying disease progression No difference after 2 years of treatment between groups on the Expanded Disability Status Scale or on any secondary endpoints

48 Case history 42 yo WF diagnosed with MS in 1996, initial symptoms left sided tingling and numbness BETASERON , discontinued (patient was stable no longer wanted to continue medication) Relapse after four years, numbness in legs Off therapy until 2006

49 Case history Received Copaxone from October 2006 to February 2007, discontinued due to allergic reaction December 2006: Relapse with left leg parasthesias and back pain April 2007 to September 2007: Avonex along with pulse steroids from June to September 2007 for increased lesion load on brain MRI September 2007: Relapse with dizziness and gait problems, MRI showed new midbrain lesion

50 RRMS with breakthrough disease

51 Breakthrough disease: Treatment approach Check compliance Check neutralizing antibodies Positive Copaxone might be a better choice Switching Between interferon products and glatiramer acetate: no studies to support Switch to Tysabri Combination therapy for suboptimal responders is also common but not supported by strong evidence Symptomatic therapy and rehabilitation Rudick et al, CNS Drugs. 2008;22(10): Malucchi et al, Neurology. 2008;70(13 pt 2):

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54 Breakthrough disease in MS: Treatment options Cyclophosphamide (Cy) is an alkylating agent, high doses of Cy produce marked immunosuppression and an anti-inflammatory immune deviation Cy is most effective in young patients, with very active MS frequent relapses, rapid accumulation of disability, and gad+ lesions on brain MRI Monthly intravenous pulses of Cy for 1 year, followed by bimonthly pulses for the second year are a well-tolerated protocol in MS Most side effects (mild alopecia, nausea and vomiting, and cystitis) are transient, dose dependent, and reversible. Permanent amenorrhoea and bladder cancer have rarely been described As second-line therapy, Cy can be used in non-responders to IFN-beta or glatiramer acetate As induction therapy, a short course (6-12 months) of Cy can precede immunomodulatory drugs in selected patients with an aggressive MS onset Rinaldi et al, Neurol Sci Oct;30 Suppl 2:S171-3

55 Breakthrough disease in MS: Treatment options Mitoxantrone (MTX) is a synthetic antineoplastic cytotoxic drug, active both on proliferative and non-proliferative cells The efficacy of MTX has been suggested by many open-label or observational studies and demonstrated in four randomized controlled clinical trials It is indicated for reducing neurological disability and the frequency of clinical relapses in patients with progressive relapsing and worsening relapsing-remitting MS patients The short-term adverse events Nausea/vomiting, alopecia, an increased risk of urinary and respiratory tract infections, phlebitis, transitory leukopenia, amenorrhea in female patients and infertility Most serious risks of the drug Cardiotoxicity and leukaemia, whose incidence seems to be higher than previously reported Martinelli et al, Neurol Sci Oct;30 Suppl 2:S167-70

56 Corticosteroids in treatment of MS Chronic use of high dose intravenous methylprednisolone (IVMP) in patients with MS may limit brain atrophy progression over the long-term In patients with RR-MS, treatment with pulses of IVMP (given every 4 months for 3 years and then every 6 months for the subsequent 2 years) vs. IVMP only for relapses slows development of T1 black holes prevents or delays whole-brain atrophy prevents or delays disability progression Zivadinov et al, Neurology Oct 9;57(7):

57 Corticosteroids in treatment of MS NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) Multicenter, randomized trial in RRMS patients with breakthrough disease on Rebif Oral 200 mg methylprednisolone or placebo for 5 consecutive days every 4 weeks for 96 weeks 62% reduction in relapse rates Sorensen et al, Lancet Neurol Jun;8(6):519-29

58 Corticosteroids in treatment of MS However recent ACT trial with weekly IFNβ-1a 30 µg IM and adjunctive steroid therapy was negative Patients with continued disease activity on weekly IFNβ- 1a 30 µg IM were randomized in a 2 x 2 factorial design to adjunctive weekly placebo or MTX 20 mg PO, with or without bimonthly IVMP 1,000 mg/day for 3 days No benefit of adding low-dose oral methotrexate or every other month IV methylprednisolone to interferon beta-1a in relapsing-remitting multiple sclerosis Cohen et al, Neurology 2009;72:

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61 Progressive MS: Conclusion Disease-modifying drugs for relapsing-remitting multiple sclerosis are only partly effective Breakthrough disease common despite treatment Breakthrough disease is predictive of continued disease activity and a poor prognosis More aggressive therapy warranted in these patients Randomized controlled trials of alternative monotherapies or combination therapies needed Not many options for progressive MS Symptomatic therapy and rehabilitation

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